Clinical impact of the radiological indeterminate for usual interstitial pneumonia pattern on the diagnosis of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease associated with significant morbidity and mortality. The international clinical practice guidelines for the diagnosis of IPF have recently been revised. METHODS: In this single-center retrospective study conducted between June 2006 and March 2018, 27 patients with a newly classified indeterminate for usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) who had undergone surgical lung biopsy were enrolled at the Japanese Red Cross Medical Center. Clinical and pathological characteristics and prognosis were retrospectively analyzed from patient records. RESULTS: On the basis of multidisciplinary discussion (MDD), IPF was diagnosed in six patients (22%), unclassifiable interstitial pneumonia in 5 (19%), chronic hypersensitivity pneumonitis in 10 (37%), collagen vascular disease-associated interstitial lung disease in 5 (19%), and lymphoproliferative disorder in 1 (4%) patient. Ground-glass opacity, peribronchovascular distribution, upper or middle lobe distribution, mosaic attenuation, consolidation patterns, and honeycombing were found on HRCT. Histological UIP or probable UIP was observed in seven patients. The median survival time from the initial visit was 2770 days (92.3 months). There was a significant difference in survival time in the GAP stage and honeycombing on HRCT according to the log-rank test. CONCLUSIONS: Patients with an indeterminate for UIP pattern on HRCT were more likely to have non-IPF than IPF through pathological diagnosis and MDD. GAP stage and honeycombing on HRCT may be significant risk factors for all-cause mortality.

Impact of preoperative pathological confirmation on surgical and postoperative outcomes of lung resection for early stage lung cancer.

INTRODUCTION: The frequency of detection of peripheral pulmonary lesion (PPL) in suspected early lung cancer has been increasing, and whether preoperative pathological diagnosis (PPD) for small PPLs should always be established before their surgical resection can become a worrisome problem for physicians. The aim of the study was to clarify the impact of obtaining PPD on surgical and postoperative outcomes of lung resection for early stage lung cancer. MATERIAL AND METHODS: This was a retrospective review of cases that underwent surgical resection for known or suspected primary lung cancer presenting pathological stage 0 or I, enrolled from June 2006 to May 2016. The patients divided into two groups according to PPD group (n = 57) and non-PPD group (n = 157) were compared. The procedure, node dissection, operation time, amount of bleeding, postoperative complications, postoperative length of stay, and postoperative recurrences were analyzed. RESULTS: Among the 214 patients, no significant differences in operation time (248.5 ± 88.6 versus 257.6 ± 89.0, min, mean ± SD, p = 0.328), amount of bleeding (195.3 ± 176.5 vs 188.1 ± 236.1, ml, p = 0.460), postoperative complication (5.2% vs 4.5%, p = 0.728), postoperative length of stay (10.6 ± 6.3 vs 10.4 ± 5.3, days, p = 0.827), or postoperative recurrences (21.0% vs 17.2%, p = 0.550) were seen between PPD and non-PPD groups. CONCLUSION: Therefore, PPD had less impact on surgical and postoperative outcomes of pathological stage 0 or I lung cancer; direct surgical resection without non-surgical biopsy would be acceptable with careful selection of cases.

Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers.

The phosphatidylinositol 3-kinase (PI3K) pathway is a promising therapeutic target for various cancers. BGT226 is a pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor. The tolerability and pharmacokinetics/pharmacodynamics of BGT226 were investigated in a phase I study in Japanese patients with advanced solid cancers. BGT226 was orally administered on days 1, 3, and 5 of each week. The initial dose of 10 mg was subsequently escalated to 20, 40, 80, and 100 mg in a cohort of three patients. Pharmacokinetics and pharmacodynamics were investigated using plasma, normal skin, and tumor samples. A total of 18 patients were enrolled and evaluated. The most frequently reported toxicities were diarrhea, nausea, decreased appetite, vomiting, and fatigue. They were all grade 1 or 2, and no dose-limiting toxicity was observed. However, all six patients treated at 100 mg experienced diarrhea and nausea, while two experienced a dose reduction and/or interruptions during the study. Two of five patients who exhibited stable disease continued the study treatment for ≥ 16 weeks. The absorption of BGT226 was rapid, and systemic exposure increased in a dose-dependent manner. Treatment with BGT226 did not change any of the biomarkers in neither normal skin nor tumor tissues. BGT226 was tolerated up to 100 mg three times a week in Japanese patients with solid cancers, without difference in toxicity profiles and pharmacokinetics compared to Western patients.

Rapid effects of benralizumab on severe asthma during surgery for residual tumor after advanced lung squamous cell carcinoma treatment with pembrolizumab.

Severe bronchial asthma is a chronic disorder of the airways that may be accompanied by comorbid diseases. Invasive treatment, including surgery, in patients with severe asthma has limitations depending on the degree of control of the asthma. A 71-year-old woman was diagnosed with squamous cell carcinoma with high programmed death-ligand 1 (PD-L1) expression and cT3N0M1a. After 13 cycles of pembrolizumab every 3 weeks, chest computed tomography (CT) revealed a dramatic decrease in the lesion size in the left upper lobe, but the size of the lesion in the right lower lobe was significantly increased. The pathological findings of the right residual tumor by CT-guided transthoracic needle biopsy (CTNB) revealed squamous cell carcinoma with no PD-L1 expression, and right lower lobectomy was recommended. However, because the patient had frequent asthma attacks and cough, surgery was considered risky. Increased blood eosinophil count was observed, and benralizumab was administered for asthma control. The symptoms disappeared 2 days after benralizumab administration, and peak flow increased. Surgery was performed 5 days after benralizumab administration. There was a marked reduction in the eosinophil count of the surgical tissue compared with the preoperative CTNB tissue. No asthma attacks were observed during and after surgery, and the control of asthma and lung cancer was stable. Benralizumab is considered promising for the treatment of eosinophilic severe uncontrolled asthma.

Management and utility of transbronchial lung cryobiopsy in Japan.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC), which is transbronchial lung biopsy performed using a cryoprobe, has emerged as a new method for obtaining lung tissue specimens for diagnosing pulmonary diseases. TBLC has been widely performed, and many reports have documented its safety and feasibility in diagnosing pulmonary diseases such as lung cancer and diffuse parenchymal lung disease. However, to date, no reports have yet been published from Japan. Therefore, the purpose of this study was to describe our experience with TBLC in daily practice in Japan and compare it with those reported in previous studies from other countries. We also evaluated the efficacy and feasibility of TBLC. METHODS: We retrospectively evaluated the clinical records of 50 consecutive patients who had undergone TBLC between November 2017 and May 2018 at the Japanese Red Cross Medical Center. Demographic data, procedure details, and the diagnostic yield were analyzed. RESULTS: We analyzed the records of 50 patients who underwent diagnostic TBLC. Their median age was 71 years, and they included 34 men (68%). The median maximal diameter of the cryobiopsy specimens was 5.3 mm (range, 2.0-23.0 mm), and the median area of the cryobiopsy specimens was 15.5 mm2 (range, 3.0-136.5 mm2). The rate of obtaining adequate specimens was 91%, and the pathological diagnostic yield was 76%. No complications were observed, except for one case of pneumonia. CONCLUSIONS: This is the first report from Japan analyzing the efficacy and feasibility of TBLC in daily clinical practice. TBLC was considered efficacious, safe, and feasible for Japanese patients with various lung diseases.

Sarcoid Myositis with Anti-Ku Antibody Consistent with both Sarcoidosis and Polymyositis.

We herein describe a case of sarcoid myositis with anti-Ku antibody positivity. Pathological findings of the muscle were compatible with sarcoidosis, but could not be completely distinguished from myositis diseases that arise from other causes. According to a physical examination, pathological findings, the detection of anti-Ku antibody and the human leukocyte antigen (HLA)-DPB1 allele, we strongly suspected that the patient developed both sarcoidosis and polymyositis. Sarcoidosis is often complicated by autoimmune diseases. This case suggests the possibility that sarcoidosis and other autoimmune diseases may have common causal genetic factors.

Pathophysiological Implication of Computed Tomography Images of Chronic Pulmonary Aspergillosis.

Chronic pulmonary aspergillosis (CPA) is a refractory disorder that needs long-term antifungal treatment and occasionally results in fatal respiratory failure and hemoptysis. However, the pathological features of the disorder have not been thoroughly delineated. Thirty cases were therefore analyzed clinically and histologically to elucidate the pathophysiology of CPA. The subjects comprised 14 individuals who underwent surgical removal and 16 patients who died. No subject exhibited a severely immunocompromised state. The main symptoms included cough, hemosputum, and dyspnea. Chest computed tomography (CT) findings revealed a cavity, fungus ball, and consolidation and/or ground glass opacity (GGO); 27 serial CT scans showed enlarged consolidation and/or GGO (70%), dilatation of the cavity (26%), and extension to the opposite lung (22%). Histopathological findings revealed a cavity with ulceration, bronchitis, and various degrees of organizing pneumonia (OP) that were correlated with the area of consolidation and GGO on the CT scan. The essential pathophysiology of CPA can be understood as an active state of ulceration of the cavity and/or erosive bronchitis caused by contact with the fungus ball, which may play a significant role in the development of OP. Consequently, OP is thought to reflect respiratory failure that relates to the prognosis of CPA.

An autopsy study of combined pulmonary fibrosis and emphysema: correlations among clinical, radiological, and pathological features.

BACKGROUND: Clinical evaluation to differentiate the characteristic features of pulmonary fibrosis and emphysema is often difficult in patients with combined pulmonary fibrosis and emphysema (CPFE), but diagnosis of pulmonary fibrosis is important for evaluating treatment options and the risk of acute exacerbation of interstitial pneumonia of such patients. As far as we know, it is the first report describing a correlation among clinical, radiological, and whole-lung pathological features in an autopsy cases of CPFE patients. METHODS: Experts retrospectively reviewed the clinical charts and examined chest computed tomography (CT) images and pathological findings of an autopsy series of 22 CPFE patients, and compared these with findings from 8 idiopathic pulmonary fibrosis (IPF) patients and 17 emphysema-alone patients. RESULTS: All patients had a history of heavy smoking. Forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC%) was significantly lower in the emphysema-alone group than the CPFE and IPF-alone groups. The percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) was significantly lower in the CPFE group than the IPF- and emphysema-alone groups. Usual interstitial pneumonia (UIP) pattern was observed radiologically in 15 (68.2%) CPFE and 8 (100%) IPF-alone patients and was pathologically observed in all patients from both groups. Pathologically thick-cystic lesions involving one or more acini with dense wall fibrosis and occasional fibroblastic foci surrounded by honeycombing and normal alveoli were confirmed by post-mortem observation as thick-walled cystic lesions (TWCLs). Emphysematous destruction and enlargement of membranous and respiratory bronchioles with fibrosis were observed in the TWCLs. The cystic lesions were always larger than the cysts of honeycombing. The prevalence of both radiological and pathological TWCLs was 72.7% among CPFE patients, but no such lesions were observed in patients with IPF or emphysema alone (p=0.001). The extent of emphysema in CPFE patients with TWCLs was greater than that in patients without such lesions. Honeycombing with emphysema was also observed in 11 CPFE patients. CONCLUSIONS: TWCLs were only observed in the CPFE patients. They were classified as lesions with coexistent fibrosing interstitial pneumonia and emphysema, and should be considered an important pathological and radiological feature of CPFE.

Diagnostic performance of interferon-gamma release assays in elderly populations in comparison with younger populations.

An understanding of the diagnostic performance of interferon-gamma release assays (in terms of parameters such as specificity, positive predictive value, and likelihood ratio) is important in the diagnosis of active tuberculosis in elderly Japanese patients because the high proportion of a prior history of tuberculosis among these patients can lead to misleading results. To elucidate the diagnostic performance of such assays, we examined the results of the QuantiFERON-TB Gold In-Tube test (QFT-GIT) in 65 patients in a younger group, and 52 patients in an elderly group who were suspected of having active tuberculosis and who had received the QFT-GIT. The median ages of the younger patients and elderly patients were 54 and 78 years, respectively. Among patients with active tuberculosis, the number of those with positive results on the QFT-GIT was similar in the two age groups [15 out of 17 (88.2 %) in the younger patients compared with 7 out of 8 (87.5 %) in the elderly patients]. However, in the patients with other diseases the number of those with positive QFT-GIT results was significantly different in the younger and elderly groups, being 6.3 and 27.3 %, respectively (P = 0.01). Although the sensitivity, negative predictive value, and negative likelihood ratio were similar in the two groups, the specificity, positive predictive value, and positive likelihood ratio were significantly lower in the elderly patients, being 72.7% (95 % confidence interval [CI], 57.2-85.0) compared with 93.8% (95 % CI, 82.8-98.7), 36.8% (95 % CI, 16.3-61.6) compared with 83.8% (95 % CI, 58.6-96.4), and 3.21 (95 % CI, 1.85-5.56) compared with 14.12 (95 % CI, 4.66-42.81), respectively. In the elderly patients with positive results on the test, a comparison of clinical data between those with active tuberculosis and those with other diseases demonstrated that the only clinical parameter showing a significant difference between these two groups was the radiological finding of small nodules in the patients with active tuberculosis (P < 0.01). The QFT-GIT may be less accurate in elderly patients, and radiological findings can be helpful in the clinical evaluation of patients with positive results on the test.

Mixed-type multicentric Castleman's disease developing during a 17-year follow-up of sarcoidosis.

Multicentric Castleman's Disease (MCD) is a systemic disease characterized by generalized lymphadenopathy and the proliferation of plasma cells. The development of MCD in a patient with preexisting sarcoidosis has not been previously reported. We herein describe a case of MCD developing in a 78-year-old woman with a 17-year history of sarcoidosis. The patient's serum interleukin-6 (IL-6) levels were only slightly elevated; however, the IL-6 levels in the fluid of both pleural effusion and ascites were markedly elevated. The administration of steroid-pulse therapy and prednisolone was ineffective in treating the MCD, although treatment with tocilizumab proved highly effective.

Upper gastrointestinal sarcoidosis: report of three cases.

Involvement of the upper gastrointestinal tract in sarcoidosis is rare, and an optimal treatment regimen remains to be determined. Here, we report 3 cases of upper gastrointestinal sarcoidosis in Japanese patients aged 57-70 years with or without epigastric symptoms and describe the clinical features, laboratory data, and upper endoscopy and pathological findings. Upper gastrointestinal sarcoidosis was diagnosed based on the presence of noncaseating epithelioid cell granuloma in the lamina propria in the stomach or duodenum. In conclusion, the possibility of upper gastrointestinal sarcoidosis should be considered in patients with epigastric symptoms and a history of sarcoidosis, even in those with stable disease.

[Two cases of microscopic polyangitis with preceding interstitial pneumonia diagnosed by surgical lung biopsy].

We encountered 2 cases of microscopic polyangitis (MPA) with preceding interstitial pneumonia. The patients were elderly men, and radiological findings showed a UIP pattern in both cases. Furthermore, ANCA-associated vasculitis had been suspected since the first admission in case 1, because MPO-ANCA tests were positive, and the surgical lung biopsy revealed vasculitis in a honeycomb lesion. A diagnosis of idiopathic pulmonary fibrosis was made in case 2 because no findings of vasculitis were pathologically confirmed, and MPO-ANCA was not examined. Both patients were followed up without any treatment, but steroid therapy with immunosuppressants was initiated after a diagnosis of MPA was made from a renal failure complication. Remission continued in case 1, but patient 2 died due to a pulmonary hemorrhage complication, despite some temporary improvements. An autopsy revealed massive alveolar hemorrhage and neutrophil infiltration in the alveolar walls that suggested pulmonary capillaritis, in spite of the absence of pathological evidence, which was not detected in the honeycomb lesions. These 2 cases indicate that MPO-ANCA should be examined in the follow-up of chronic interstitial pneumonia. Furthermore, it should be assumed that the size of involved blood vessels, their distribution and the timing of occurrence may be different in individual case of ANCA-associated interstitial pneumonia.

[Clinical comparison of male and female patients with pulmonary disease caused by Mycobacterium avium complex (P-MAC)].

OBJECTIVES: The objective of this study was to clarify clinical feature of Pulmonary Mycobacterium avium complex disease (P-MAC). METHOD: The present study was performed in 120 patients with P-MAC diagnosed during the period from January 2000 to March 2007. We divided P-MAC patients into four groups by the clinical disease type and gender, and retrospectively examined the clinical characteristics. RESULTS: The subjects were 15 male (NB-M) and 71 female (NB-F) patients with nodular bronchiectatic disease (NB), and 24 male (FC-M) and 10 female (FC-F) patients with fibrocavitary disease (FC). The average age was lowest in the NB-F group (58.0 yrs), and highest in the FC-M group (65.8 yrs). There were 17 patients in the FC-M group and only two patients in the FC-F group with a history of smoking. The average body mass index (BMI) was 16.9, with the lowest value in the FC-F group. In the FC-M group, most of the patients had underlying pulmonary disease, whereas in the FC-F group, only four patients had underlying old pulmonary tuberculosis. The average anterior-posterior dimension was 75.2 mm, being lowest in the FC-F group, and more than 90 mm in the other groups. The proportion of refractory cases was lowest in the NB-M group. CONCLUSION: We thought that we were able to clarify characteristics of patients with disease caused by MAC by analyzing the types of the disease separately in men and women.

[Evaluation of KL-6 CLEIA reagent].

KL-6 is a high-molecular-weight sialylated glycoprotein, classified as a cluster 9 pulmonary cell antigens, and is a sensitive marker for the clinical diagnosis of interstitial pneumonia and its activity, especially in the acute phase. Additionally, it is necessary to diagnosis that patient was not pneumothirax, pulmonary thromboembolism and heart failure. In this study, we evaluated a new assay system based on chemiluminescence EIA (CLEIA) on a fully automated analyzer. Both plasma and serum samples were used, and the master calibration method was applied, eliminating the need for a standard curve preparation. The assay time was shortened to less than 1 hour. Good correlations were observed between this assay and conventional assay kits, y = 1.094x-6.849, r = 0.986 using 326 samples, and between serum and plasma y = 0.997x-1.211, r = 0.997 using 225 paired samples. In addition, the alteration of KL-6 concentration in patients undergoing chemotherapy treatment resulted in similar results that with conventional kits, and elevated KL-6 concentrations were observed in samples from patients with interstitial pneumonia. These results underscore the usefulness of this new assay kit as a rapid test, particularly for the medical examination of outpatients and the treatment of emergency cases in the acute phase of interstitial pneumonia.

[Aspergillosis].

Aspergillosis occurs as an opportunistic infection, and is known as the disease whose diagnosis and treatment are particularly difficult. Japan's first guidelines for the diagnosis and management of invasive fungal infection were revised in 2007, and it is expected that the guidelines may encourage the standardization of the management of fungal infection. The algorithm of the guidelines is composed of three categories of diagnosis: "Proven infection", "Clinically documented infection or Probable infection" and "Possible infection"; and 2 categories of therapy: "empiric", and "targeting" therapy. The early diagnosis and establishment of treatment methods for, pulmonary aspergillosis, neither of which are adequate presently, are a pressing need. However, the recent development of several serological diagnostic methods and launching new antifungal drugs changes the diagnosis and therapeutic strategy for pulmonary aspergillosis.

Disseminated cryptococcosis complicated with bilateral pleural effusion and ascites during corticosteroid therapy for organizing pneumonia with myelodysplastic syndrome.

An 83-year-old man with myelodysplastic syndrome was admitted to our hospital due to dyspnea and abnormal shadows on chest X-ray films during corticosteroid therapy for organizing pneumonia. He was diagnosed as having disseminated cryptococcosis with pulmonary lesions after detecting Cryptococcus neoformans. Both bilateral pleural effusion with or without ipsilateral pulmonary lesions and ascites ensued, and it was assumed that both direct involvement and serositis were associated with the fluid accumulation. Cryptococcal yeast was only detected in the right pleural effusion, and the titer of cryptococcal antigen was quite different between body cavities, even though it was positive in all sites.

[Case of acute bird fancier's lung caused by a yellow-shouldered Amazon bird associated with lung cancer].

A 69-year-old man was admitted to our hospital complaining of generalized weakness and cough for one month. Chest computed tomography (CT) demonstrated bilateral ground-glass opacities and a nodule in right S6 about 11mm in diameter with multiple mediastinal lymph node swellings. After admission the patient's symptoms improved without therapy and examination of the bronchoalveolar lavage fluid (BALF) and transbronchial lung biopsy (TBLB) revealed findings compatible with acute hypersensitivity pneumonitis. We did not consider that the acute hypersensitivity was caused by the patient's Amazon bird, because he had been breeding them for 40 years. However after obtaining a careful history, it became clear that close and frequent contact with the bird had occurred for the first time in the previous year. On the basis of the anti-bird excreta antibody found in the patient's serum and BALF, we diagnosed this case as a case of acute bird fancier's lung caused by the yellow-shouldered Amazon bird. We diagnosed the nodule in right S6 as lung adenocarcinoma by a thoracoscopic lung biopsy, and performed lower lobe lobectomy. We considered that the mediastinal lymph node swellings were caused by hypersensitivity pneumonitis.